Abstract
FARP1 is a multi-domain protein that is involved in regulating neuronal development through interacting with cell surface proteins such as class A Plexins and SynCAM 1. The N-terminal FERM domain in FARP1 is known to both promote membrane localization and mediate these protein interactions, for which the underlying molecular mechanisms remain unclear. Here we determined the crystal structures of the FERM domain of FARP1 from zebrafish, and those of FARP2 (a close homolog of FARP1) from mouse and zebrafish. These FERM domains adopt the three-leaved clover fold that is typical of all FERM domains. Our structures reveal a positively charged surface patch that is highly conserved in the FERM domain of FARP1 and FARP2. In vitro lipid-binding experiments showed that the FARP1 FERM domain binds specifically to several types of phospholipid, which is dependent on the positively charged surface patch. We further determined through cell-based analyses that this surface patch on the FERM domain underlies the localization of FARP1 to the plasma membrane, and that FERM domain interactions recruit it to postsynaptic sites in neurons.
Highlights
FARP1 (FERM, RhoGEF and pleckstrin domain-containing protein 1) and its close homolog FARP2 were identified as guanine nucleotide exchange factors (GEFs) for RhoGTPases that play regulatory roles in neuronal development[1,2,3,4]
The results showed that the FERM domain of human FARP1 (hFARP1) bound robustly to a variety of phospholipids, including phosphatidylinositol (PI)-3-phospate (PI3P), PI4P, PI5P, PI(3,4)P2, PI(3,5)P2, PI(4,5)P2, PI(3,4,5) P3, and Phosphatidylserine (PS), but not Lysophosphatidic Acid (LPA), Lysophosphocholine (LPC), PI, Phosphatidylethanolamine (PE), Phosphatidylcholine (PC), Sphingosine-1-phosphate (S1P), or Phosphatidic Acid (PA) (Fig. 3)
Class A Plexins have been shown to interact with the FERM domains of FARP1 and FARP2
Summary
FARP1 (FERM, RhoGEF and pleckstrin domain-containing protein 1) and its close homolog FARP2 were identified as guanine nucleotide exchange factors (GEFs) for RhoGTPases that play regulatory roles in neuronal development[1,2,3,4]. FARP1 has been shown to regulate synapse number and dendritic spine morphology[6,8]. This function of FARP1 is mediated, at least in part, by a direct interaction with the synaptogenic adhesion molecule SynCAM 18. We determined the crystal structures of the FERM domain of FARP1 from zebrafish as well as those of FARP2 from mouse and zebrafish These structures and the associated biochemical and cell-biological analyses provide mechanistic insights into the interactions of these FERM domains with the plasma membrane and cell surface receptors, supporting FERM domain roles in the synaptic recruitment of FARP1 in neurons
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